Aortic valve disease and treatment: The need for naturally engineered solutionsIntroductionAortic valve structure and physiologyRoot structureValve cusp structureCoordinated functionIn vivo kinematicsCusp tissue biomechanicsAortic root tissue biomechanicsRelationship to tissue microstructureNormal aortic valve biologyAortic valve endothelial cellsShear stress and endothelial functionSide specific VEC behaviorsAortic valve interstitial cellsMechanical stress and VIC phenotypeIntercellular crosstalkClinical and societal burden of aortic valve diseaseDiagnosis and monitoring of AVD progressionEchocardiographyAVD biomarkersTreatment of valve diseaseValve replacementPharmacological treatmentAnimal models of aortic valve diseaseSpontaneously occurringDiet-inducedChemically-inducedTransgenic modelsSurgical modelsMechanisms of calcific aortic valve diseaseDistinguishing pathobiologyGenetic predispositions to CAVDBicuspid aortic valve (BAV)Marfan syndromeWilliams syndromeCollagen mutations22q11 deletionHolt–Oran syndromeNoonan syndromeDown's syndromeCaveatOther causes of aortic valve diseaseRheumatic feverInfective endocarditisCellular and molecular mechanisms of CAVDEndothelial dysfunctionInterstitial cell activation and matrix remodelingLipid metabolismRenin-angiotensin and kallikrein-kinin system balanceSerotonin metabolismBiomechanical changesAngiogenesisCalcificationOsteogenic differentiationDystrophic calcificationIs it really “bone”?Other contributorsStem/progenitor cellsEndothelial to mesenchymal transformation (EMT)Potential molecular mediators of valve specific calcificationNOTCH1Nitric oxideAortic valve tissue engineeringDesign criteriaDesign pathTEHV approachesDecellularized valvesBiodegradable synthetic polymer TEHVBiological protein based TEHVIn vivo tissue engineered valvesHybrid TEHV manufacturing strategiesCell sources for TEHVConclusionsAcknowledgementsReferencesAortic valve disease and treatment: The need for naturally engineered solutions☆Jonathan T. Butcher⁎, Gretchen J. Mahler, Laura A. HockadayDepartment of Biomedical Engineering, Cornell University, Ithaca, NY, USAabstractarticle infoArticle history:Received 12 November 2010Accepted 14 January 2011Available online xxxxKeywords:AtherosclerosisStenosisCalcificationRisk factorsHeterogeneousBiomarkersCongenital heart defectsGenetic mutationsAnimal modelsTissue engineeringBiomechanicsEndothelialInterstitialClinical trialsDrug discoveryThe aortic valve regulates unidirectional flow of oxygenated blood to the myocardium and arterial system. Thenatural anatomical geometry and microstructural complexity ensures biomechanically and hemodynamicallyefficient function. The compliant cusps are populated with unique cell phenotypes that continually remodeltissue for long-term durability within an extremely demanding mechanical environment. Alteration fromnormal valve homeostasis arises from genetic and microenvironmental (mechanical) sources, which lead tocongenital and/or premature structural degeneration. Aortic valve stenosis pathobiology shares some featuresof atherosclerosis, but its final calcification endpoint is distinct. Despite its broad and significant clinicalsignificance, very little is known about the mechanisms of normal valve mechanobiology and mechanisms ofdisease. This is reflected in the paucity of predictive diagnostic tools, early stage interventional strategies, andstagnation in regenerative medicine innovation. Tissue engineering has unique potential for aortic valvedisease therapy, but overcoming current design pitfalls will require even more multidisciplinary effort. Thisreview summarizes the latest advancements in aortic valve research and highlights important futuredirections.© 2011 Published by Elsevier B.V.Contents1. Introduction ............................................................... 02. Aortic valve structure and physiology ................................................... 02.1. Root structure .......................................................... 02.2. Valve cusp structure ....................................................... 02.3. Coordinated function ....................................................... 02.4. In vivo kinematics ........................................................ 0Advanced Drug Delivery Reviews xxx (2011) xxx–xxxAbbreviations: 2D, two-dimensional; 3D, three-dimens ional; 5-HT, serotonin; 5-HTT, serotonin transporter; αSMA, Alpha smooth muscle actin; ACE, angiotensin convertingenzymes; ADHD, attention-deficit hyperactivity disorder; ANF, atrial natriuretic factor; ANGII, angiotensin II; APOE, Apolipoprotein E; ARB, angiotensin receptor blocker; AT1,angiotensin II Type 1; AVD, Aortic valve disorders; B1 and B2, bradykinin receptors; BAV, bicuspid aortic valve; BK, bradykinin; BMP, bone morphogenic protein; BMSC, bone marrowderived mesenchymal stem cells; BPV, bioprosthetic valve; CAD, computer aided design; CAVD, calcific aortic valve disease; CHD, congenital heart defect; CVD, cardiovasculardisease; COL, collagen; CX40, connexin 40; DGEA, collagen-derived peptide motif; EC, endothelial cells; ECM, extracellular matrix; EDMP, Endocardial derived mesenchymalprogenitors; EDS, Ehlers–Danlos syndrome; EDTA, Ethylenediaminetetraacetic acid; ELN, elastin; EMT, endothelial to mesenchymal transformation; eNOS, endothelial nitric oxidesynthase; FBN1, fibrillin; FDA, Federal Drug Administration; FZD, frizzled receptors; GAG, glycosaminoglycans; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; HVD, heartvalve disease; KKS, kallikrein-kinin system; LDL, low density lipoprotein; LDLr, low density lipoprotein receptor; LPS, lipopolysaccharide; MDA, N-demethylated metabolite3,4-methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymetham-phetamine; MGP, matrix gla protein; MMP, matrix metalloproteases; MPV, mechanical prosthetic valves;NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; NFκB, nuclear factor kappa B; OPG, osteoprotegerin; OPN, osteopontin; P4HB, poly-4-hydroxybutyrate; PEG-DA,poly (ethylene glycol) diacrylate; PGA, polyglycolic acid; PHO, polyhydroxyalkanoate; PLGA, poly (lactic-co-glycolic acid); PLLA, poly (L-lactic acid); RANK, receptor activator ofnuclear factor kappa B; RANKL, receptor activator of nuclear factor kappa B ligand; RAS, renin-angiotensin system; RGDS, fibronectin-derived peptide motif; ROS, reactive oxygenspecies; RVD, rheumatic valve disease; SDS, sodium dodecyl sulfate; SMM, smooth muscle myosin; SPARC,
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